Immune Inhibitory Ligand CD200 Induction by TLRs and NLRs Limits Macrophage Activation to Protect the Host from Meningococcal Septicemia

Abstract

Macrophage activation is essential for protection against bacterial pathogens but needs to be regulated to prevent damage to the host. We show a key role for the immune inhibitory receptor CD200R and its ligand CD200 in the context of infection with the Gram-negative human pathogen Neisseria meningitidis. N. meningitidis induced CD200 but downregulated CD200R on macrophages in a manner dependent on Neisserial lipopolysaccharide, Toll-like receptor-4 (TLR-4), and the MyD88 pathway but independent of a known Neisserial receptor, scavenger receptor A (SR-A). Agonists of the pattern-recognition receptors nucleotide oligomerization domain 2 (NOD2) and NACHT-LRR protein 3 (NALP3) also induced CD200. The NF-κB member c-Rel was essential for TLR-, NOD2-, and NALP3-mediated induction of CD200. CD200(-/-) animals showed higher lethality in response to experimental meningococcal septicemia, induced higher levels of proinflammatory cytokines, and recruited increased numbers of activated leukocytes, despite comparable bacterial clearance. Thus CD200 is induced by TLR-, NOD2-, and NALP3-mediated pathways, limiting their function and protecting the host from excessive inflammation.

Long Term Potentiation Is Impaired in Membrane Glycoprotein CD200-deficient Mice

“…The present findings in glia mirror those observed in peritoneal macrophages; thus, stimulation with LPS and peptidoglycan and also poly(I:C) increased release of TNF␣ and IL-6 to a greater extent in macrophages prepared from CD200 Ϫ/Ϫ mice compared with wild type mice (26). Similarly, alveolar macrophages prepared from CD200 Ϫ/Ϫ mice, when stimulated ex vivo with LPS or IFN␥, expressed more MHCII and released more inflammatory cytokines than macrophages from wild type mice (27).…”

CD200-CD200R signaling suppresses anti-tumor responses independently of CD200 expression on the tumor

“…It is likely that these processes are regulated by CD200-CD200R through the same mechanism. Notably, infection of Cd200 À/À mice with Neisseria meningitides or influenza virus causes increased production of pro-inflammatory cytokines, including IL-1b, IL-6, tumor necrosis factora and interferong (Snelgrove et al, 2008;Mukhopadhyay et al, 2010). In our endogenous tumor model we also observed higher levels of the pro-inflammatory cytokines IL-1b and IL-6 in tumor-draining LN DCs derived from Cd200 À/À mice.…”

Inhibition of SIRPα in dendritic cells potentiates potent antitumor immunity

“…16 Interaction of CD47 with SIRPa negatively regulates phagocytosis of host cells by macrophages. [17][18][19][20][21] Consistently, anti-CD47 antibody or engineered SIRPa variants with increased affinity for CD47 can induce potent tumoricidal activity of macrophage by antagonizing CD47 on cancer cells. 22,23 In lungs, ligation of SIRPa to macrophages by surfactant proteins is required to keep the activity of alveolar macrophages in check, thus preventing damage to the airways caused by pro-inflamatory responses.…”